The sudden outbreak of the severe acute respiratory syndrome-coronavirus (SARS-CoV-2) has spread globally with more than 1,300,000 patients diagnosed and a death toll of 70,000. Current genomic survey data suggest that single nucleotide variants (SNVs) are abundant. However, no mutation has been directly linked with functional changes in viral pathogenicity. Here we report functional characterizations of 11 patient-derived viral isolates, all of which have at least one mutation. Importantly, these viral isolates show significant variation in cytopathic effects and viral load, up to 270-fold differences, when infecting Vero-E6 cells. We observed intrapersonal variation and 6 different mutations in the spike glycoprotein (S protein), including 2 different SNVs that led to the same missense mutation. Therefore, we provide direct evidence that the SARS-CoV-2 has acquired mutations capable of substantially changing its pathogenicity.

Summary Human health is dependent upon environmental exposures, yet the diversity and variation in exposures is poorly understood. We developed a sensitive method to monitor personal airborne biological and chemical exposures and followed the personal exposomes of 15 individuals for up to 890 days and over 66 distinct geographical locations. We found that individuals are potentially exposed to thousands of pan-domain species and chemical compounds, including insecticides and carcinogens. Personal biological and chemical exposomes are highly dynamic and vary spatial-temporally, even for individuals located in the same general geographical region. Integrated analysis of biological and chemical exposomes revealed strong location-dependent relationships. Finally, construction of an exposome interaction network demonstrated the presence of distinct yet interconnected human- and environment-centric clouds, comprised of interacting ecosystems such as human, flora, pets and arthropods. Overall, we demonstrate that human exposomes are diverse, dynamic, spatiotemporally-driven interaction networks with the potential to impact human health.

The presence of autoantibodies in systemic lupus erythematosus, particularly those of the IgG subclass, have long been associated with disease onset and activity. Here we explored the prevalence of autoreactive IgE in SLE and its relevance to disease in French (n = 79) and United States (US) (n = 117) cohorts with a mean age of 41.5±12.7 and 43.6±15.3 years and disease duration of 13.5±8.5 and 16.6±11.9 years, respectively. Our findings show that approximately 65% of all SLE subjects studied produced IgE antibodies to the seven autoantigens tested. This positivity was increased to almost 83% when only those subjects with active disease were considered. SLE subjects who were positive for anti-dsDNA, -Sm, and -SSB/La -specific IgE showed a highly significant association in the levels of these antibodies with disease activity similar to that of the corresponding IgG's. A strong association of IgE autoantibodies with active nephritis was also found in the combined cohort analysis. A test of the predictive value of autoreactive IgE’s and IgGs for disease activity (SLE Disease Activity Index (SLEDAI) ≥4) revealed that the best predictors were dsDNA-specific IgE and IgG, and that the age of an SLE subject influenced this predictive model. The finding argue that the overall levels of IgE autoantibodies, independently or in combination with IgG autoantibodies, may serve as indicators of active disease.

Background Anticytokine autoantibodies occur across a range of hematologic, pulmonary and infectious diseases, however, systematic investigation of their presence and significance in autoimmune diseases is lacking. Methods Serum samples from patients with systemic lupus erythematosus (SLE) (n=199), primary Sjögren’s syndrome (SS) (n=150), rheumatoid arthritis (RA) (n=149) and healthy controls (n=200) were screened for 24 anticytokine autoantibodies using a multiplex bead-based assay. To evaluate biological activity of anticytokine autoantibodies, their ability to block cytokine-induced signal transduction or protein expression was measured. RNA sequencing was performed on whole blood in subset of controls and SLE patients. Results SLE and SS patients had striking excess of autoantibodies against interferons and the interferon-responsive chemokine interferon-inducible-protein-10 (IP-10). Only autoantibodies against type I interferon, interleukin (IL)-12 and IL-22 exhibited neutralizing activity. In SLE, anti-interferon-γ autoantibodies tracked with more disease activity, anti-double-stranded-DNA antibodies, and elevated expression of interferon-α/β-inducible genes. Conversely, SLE patients with blocking anti-interferon-α autoantibodies normalized their type I interferon gene expression signature. Anti-type III interferons (λ2, λ3), and anti-IP-10 autoantibodies were newly recognized and autoantibodies against macrophage-colony stimulating factor, IL-4, IL-7, IL-17 and IL-22, that have not been previously identified in rheumatologic conditions, were discovered. Conclusions Anticytokine autoantibodies were associated with distinct patterns of SLE, SS and RA. Anti-interferon autoantibodies were overrepresented in SLE and SS and fall into distinct functional classes with only a subset of anti-type I interferon antibodies exhibiting neutralizing activity. Anti-interferon-γ autoantibodies correlated with increased disease activity and interferon-related gene expression, suggesting that they may contribute to the pathogenesis of SLE.

What mechanisms underlie the transitions responsible for the diverse shapes observed in the living world? While bacteria display a myriad of morphologies1, the mechanisms responsible for the evolution of bacterial cell shape are not understood. We investigated morphological diversity in a group of bacteria that synthesize an appendage-like extension of the cell envelope called the stalk2,3. The location and number of stalks varies among species, as exemplified by three distinct sub-cellular positions of stalks within a rod-shaped cell body: polar in the Caulobacter genus, and sub-polar or bi-lateral in the Asticcacaulis genus4. Here we show that a developmental regulator of Caulobacter crescentus, SpmX5, was co-opted in the Asticcacaulis genus to specify stalk synthesis at either the sub-polar or bi-lateral positions. We show that stepwise evolution of a specific region of SpmX led to the gain of a new function and localization of this protein, which drove the sequential transition in stalk positioning. Our results indicate that evolution of protein function, co-option, and modularity are key elements in the evolution of bacterial morphology. Therefore, similar evolutionary principles of morphological transitions apply to both single-celled prokaryotes and multicellular eukaryotes.

In lupus-prone NZM2328 mice, a locus Cgnz1 on chromosome 1 was linked to chronic glomerulonephritis, severe proteinuria, and early mortality in females. A locus Adnz1 on chromosome 4 was linked to antinuclear antibody (ANA) and anti–double stranded DNA (dsDNA) antibody (Ab) production. In this investigation, two congenic strains, NZM2328.C57L/Jc1 (NZM.C57Lc1) and NZM2328.C57L/Jc4 (NZM.C57Lc4), were generated by replacing the respective genetic intervals containing either Cgnz1 or Adnz1 with those from C57L/J, a nonlupus-prone strain. The NZM.C57Lc1 females had markedly reduced incidence of chronic glomerulonephritis and severe proteinuria. NZM.C57Lc4 females had chronic glomerulonephritis and severe proteinuria without circulating ANA, anti-dsDNA, and antinucleosome Ab. These data confirm the linkage analysis. Unexpectedly, NZM.C57Lc1 females had little anti-dsDNA and related Ab, suggesting the presence of a second locus Adnz2 on chromosome 1. The diseased NZM.C57Lc4 kidneys had immune complexes by immunofluorescence and electron microscopy. The eluates from these kidneys did not contain ANA, anti-dsDNA, and antinucleosome Ab, indicative of the presence of non–anti-dsDNA nephritogenic Ab. Thus, breaking tolerance to dsDNA and chromatin is not required for the pathogenesis of lupus nephritis. These results reaffirm that anti-dsDNA and related Ab production and chronic glomerulonephritis are under independent genetic control. These findings have significant implications in the pathogenesis of systemic lupus erythematosus.

Identifying bacterial strains in metagenome and microbiome samples using computational analyses of short-read sequence remains a difficult problem. Here, we present an analysis of a human gut microbiome using on Tru-seq synthetic long reads combined with new computational tools for metagenomic long-read assembly, variant-calling and haplotyping (Nanoscope and Lens). Our analysis identifies 178 bacterial species of which 51 were not found using short sequence reads alone. We recover bacterial contigs that comprise multiple operons, including 22 contigs of >1Mbp. Extensive intraspecies variation among microbial strains in the form of haplotypes that span up to hundreds of Kbp can be observed using our approach. Our method incorporates synthetic long-read sequencing technology with standard shotgun approaches to move towards rapid, precise and comprehensive analyses of metagenome and microbiome samples.

Autoantibodies are of central importance in the pathogenesis of Ab-mediated autoimmune disorders. The murine lupus susceptibility locus Nba2 on chromosome 1 and the syntenic human locus are associated with a loss of immune tolerance that leads to antinuclear Ab production. To identify gene intervals within Nba2 that control the development of autoantibody-producing B cells and to determine the cellular components through which Nba2 genes accomplish this, we generated congenic mice expressing various Nba2 intervals where genes for the FcγR, SLAM, and IFN-inducible families are encoded. Analysis of congenic strains demonstrated that the FcγR and SLAM intervals independently controlled the severity of autoantibody production and renal disease, yet are both required for lupus susceptibility. Deregulated homeostasis of terminally differentiated B cells was found to be controlled by the FcγR interval where FcγRIIb-mediated apoptosis of germinal center B cells and plasma cells was impaired. Increased numbers of activated plasmacytoid dendritic cells that were distinctly CD19+ and promoted plasma cell differentiation via the proinflammatory cytokines IL-10 and IFNα were linked to the SLAM interval. These findings suggest that SLAM and FcγR intervals act cooperatively to influence the clinical course of disease through supporting the differentiation and survival of autoantibody-producing cells.